Targeting Lung-Derived Proteins as a Therapeutic Strategy Against Breast Cancer Metastasis
Abstract
Background: Breast cancer is a significant health problem worldwide, and it is currently the number one diagnosed cancer and number two cause of cancer-related deaths among American women. If detected early, traditional surgical and radiation therapy approaches have a high success rate, but once the disease spreads (or metastasizes) beyond the breast, many conventional treatments fail. In particular, the lung is one of the most common and deadly sites of breast cancer metastasis, and this has a significant impact on patient quality of life and survival. Treatment of metastasis is often done by delivering drugs to the whole body, causing toxic side effects. However, unlike other metastatic sites, the lung has the unique potential to be targeted directly by delivering drugs via inhalation, an approach that has been used in the treatment of respiratory diseases but remains underexplored in oncology. Previous Knowledge/Rationale: Dr. Allan s previous work suggests that aggressive breast cancer cells expressing a protein called CD44 on their cell surface are responsible for metastasis. Importantly, her research group has shown that these CD44+ cancer cells have a particular propensity for migrating (traveling to) and growing in the lung through specific interactions with proteins produced by the lung itself. In addition, Dr. Allan has recently developed a collaboration with Co-Investigator Dr. Löbenberg, who has extensive expertise in developing inhalable drugs that have high permeability and retention in lung, allowing local accumulation rather than diffusion throughout the body. They have shown that these drugs can be used to effectively treat lung cancer in mice with very low levels of systemic (whole body) toxicity. Objectives and Aims: In this proposal, Dr. Allan and her research team aim to understand the interactions between CD44+ breast cancer cells and CD44-interacting proteins produced by the lung microenvironment in order to determine how this helps migration and growth in the lung as part of the metastatic process. They will also team up with Dr. Löbenberg to investigate whether they can use an inhaled drug delivery approach to directly inhibit CD44-interacting proteins in the lung as an effective strategy for reducing breast cancer metastasis as well as toxic side effects. Innovative 2D and 3D simulated organ environments in culture dishes, animal models of metastasis and treatment, and inhalable drug delivery strategies will be used to carry out these studies. Applicability and Impact: This innovative proposal will lead to several potential avenues for accelerating progress towards ending breast cancer. It will address three of the overarching challenges of the Breast Cancer Research Program, including identifying why some breast cancers become metastatic; revolutionizing treatment regimens by replacing them with ones that are more effective and less toxic; and eliminating the mortality associated with metastatic breast cancer. This research will help all breast cancer patients that develop metastatic disease in their lungs, in particular patients with aggressive triple-negative disease who tend to have a high propensity for lung metastasis that results in significant morbidity and mortality. The overall goal of this project is to provide preclinical evidence that direct targeting of lung-derived proteins is an effective therapeutic strategy against breast cancer metastasis. This will be accomplished within the 3-year period of this Breakthrough Level 2 grant. These results will lay the critical groundwork needed for the next steps of translating this knowledge into the clinic by developing and testing similar inhalable drugs for human patients that directly target lung-derived proteins. Patient-related outcomes associated with improved treatment of lung metastasis are projected to be more long term (i.e., within 6-10 years). The benefits of our proposed research include the development of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710470
Entities
People
- Alison Allan
Organizations
- United States Army
- Western University